Influenza viruses pose a major threat to human health. Most widely used vaccines are made from inactivated components of viruses that are prevalent in the community. These vaccines induce strong antibody responses, with weak cell mediated immunity and provide limited protection against pandemic strains. Less common approaches include the use of live viral vectors to induce local populations of virus-specific memory CD8 T cells in the respiratory tract, which include cells that recognize highly conserved epitopes in different strains of influenza virus. We have previously shown that optimal-cell mediated immunity requires the combined activities of multiple subsets of virus-specific memory CD8 T cells, including local populations of non-circulating tissue-resident memory CD8 T cells (TRM) which are adapted for prolonged survival in peripheral tissues. Although TRM cells are widely acknowledged to make a valuable contribution to immunity, the mechanisms that drive CD8 T cell differentiation and memory development are poorly defined. We recently found that the signaling intermediate Sma and Mad related protein 4 (Smad4) participates in a novel regulatory pathway in CD8 T cells, which promotes T effector generation and suppresses CD103 expression on activated CTLs in peripheral and lymphoid tissues. This proposal is divided into four distinct, but integrated, aims which address fundamental questions about the mechanisms that elicit heterogeneous populations of memory CD8 T cells in the lungs and their role in anti-viral immunity. Molecular and cellular approaches will be used to determine whether specific steps in the immune response can be manipulated to augment immunity and are thus viable targets for local delivery of therapeutic regents which promote TRM development.